Secondary alkyl (secondary) amino alcohol esters of aryl-substituted aliphatic acids



Patented Dec. 14, 1948 SECONDARY ALKYL (SECONDARY) AIVIINO ALCOHOLESTERS OF ARIEL-SUBSTITUTED ALIPHATIC ACIDS Arthur G. Cope, Belmont,Mass, assignor to Sharp &' Dohmc; Incorporated, Philadelphia, Pa., acorporation of Maryland No'Drawing. Application October 6, 1945, SerialNo. 620,839

12 Claims. 1

This invention relatesto cinnamic, 'diphenylacetic, alpha-cyclohexylalpha:- phenyl-acetic', and alpha-phenylbutyrie acid esters-=01?secondary-alkyl(secondary) -aminoeth'anols, -propanols and -butanols,which esters are useful as local anesthetics and antispasmodics; ingeneral,

combining high effectiveness with relatively w toxicity.

The compounds or the invention are represented by the general formulaX--CGOR1-NHR, in which Rrepresentsasecondary alkyl group attached to theamino nitrogen; R'i represents the alkylene group having at least" two,three or four carbon atoms or, in other words, the divalent aliphatic.residue or the ethanol, propanol or butanol, X is selected from thestyryl radical; the diphenylmethyt radical; the.alphacyclohexyl'-alpha-phenyl methyl, andthe alphaphenylpropyl' radical.

Thus, it-is seen that both the alkylsubstituent on the amino groupandth'eaminogroup itself are secondary; and that the-- secondary aminogroup is derived from ammoniaby replacing one of its hydrogens by thesecondary-alkyiisubstituent and a second hydrogen-bythe-alkylene grouprepresented by R1. Accordingly; in' this specification and in the claimsthe expression secondary-alkyl (secondary)-amin'o is used to describethe alkyl-amino grouping ontheethanol propanoland butanol-amine'portionof the compounds of the invention and to show that the amino group isalways secondaryand that the alkyl substituent on" the amino group isalways secondary.

The secondary-alkyl substituent' on theami'no group of thealkylaminoalkanol portion of" the compounds of the invention contains atleast three carbon atoms" and-maybe open chainas isopropyl,secondary-butyl'. -pentyl",i -h"exy1, -hep-- tyl, -octyl, -nonyl,andthelike; or cycll'cas" the alicyclic groups such ascyclopent'yllcyclohexyl and the-like, and the various open'chain orcyclic groupingsmay be unsubstituted as those already mentioned or mono -orpoly-substituted'as with other alkyl groups such as in groups like '4-methylpentyl; 2,6-dimethylhep'tyl (or diisobutylmethyl), and the like aswell as 3'-ethylcyclo-- pentyl, 4-methylcyclohexyl; 4-ethyicycldhexyland the like.

The esters of the invention" are prepared by suitable reaction between 2the acidylanhydrlde or halide such astheacid: chloride or bromide ofcln'namlc acid, diphenylaceticr acid or alphaphenylbutyricacid' (as thecinnamoylr halide, diph'enylaoetyli halide alphaephenylbutyryl halide)with the desired secondary-alkyl-aminoethanol, -propanol or -butanol. Inpreparing the esters starting with an alkylaminoalkanol containing anon-tertiary alcohol group, the acidyl halide or'anhydride of theparticular acids disclosed is reacted with an addition salt of thedesired alkylaminoalkanol containing the desired secondary-alkylsubstituent on its amino group. An advantageous procedure for condensingthe acidyl compound with the salt of the aminoalkanol is to dissolve theaminoalkanol in an inert solvent such as a chlorinated lower paraffinhydrocarbon as chloroform or methylene chloride and the like and toconvert it to its addi-- tion salt such as the hydrochloride bysaturating the solution with dry hydrochloric acid gas, with cooling,and then to add to the solution an equal molal quantity of therespective aci'dyl halide as cinnamoyl'chloride dissolved in an equalquantity of the same solvent, and'heating the reaction mixture underreflux at 50 to C., or higher, but preferably at the lower temperaturerange, then cooling the reaction mixture and removing the solvent undervacuum, and if the free base is desired, then treating the reactionproduct suspended in water with sufficient suitable alkali as sodiumcarbonate monohydrate to liberate the free amino ester.

The invention may be illustrated by, but not restricted to, thefollowing examples:

Example 1.2isopropylammo-ethyl alphaphenylbutyrate hydrochloride-Asolution of 0.1

mol of 2 isopropylamino-ethanol in 30 grams of chloroform was saturatedwith dry hydrogen chloride gas, with cooling. A solution of 0.1 molalpha-phenylbutyryl chloride in 30 grams of chloroform was added and thesolution was heated in a bath at 50-60 C. for four days under a refluxcondenser protected from atmosphericv moisture. Then the solvent, wasremoved by vacuum" distillation while the mixture was warmed on a waterbath. Benzene was then added to the syrupy residue and the reactionproduct crystallized out after the benzene was removed by vacuumdistillation. The crystallized solid residue was washed with anhydrousether to remove any unreacted alpha-phenylbutyryl chloride. The 2-isopropylamino-ethyl alpha-phenylbutyrate hydrochloride obtained waspurified by recrystallie zation from alcohol and ether. It melted at123-125" C.

By replacing the 2-isopropylamino-ethanol-in. the above exampleseparately by 2-(4-heptylamino)v -ethanol, 2- [4- (2,-6-dimethylheptyl)aim-- ol-ethanol, Z-cyclohexylamino-ethanol, there. is;

3 obtained the corresponding hydrochloride of the alpha-phenylbutyricacid ester: 2-(4-heptylamino) -ethyl alpha-phenylbutyrate hydrochloride,M. P. 8485 0., 2-[4-(2,6-dimethylheptyl)-aminol-ethylalpha-phenylbutyrate hydrochloride, M. P. 1l8-120 (1.,2-cyclohexylamino-ethyl.

alpha-phenylbutyrate hydrochloride, M. P. 119- 120 C. Similarly .byreplacing Z-isopropylamino-ethanol of Example 1 by any (secondary) a1-kylamino-ethanol, propanol or -butanl, such as 1-alkylamino-2-propano1s,2-a1ky1amino-1- propanols, 3-alkylamino-1-propanols,2-alkylamino-Z-methyl-l-propanols, and the like, the (secondary-alkylgroup of any of which may be,- for example, isopropyl, 3-pentyl,4heptyl, 4-(2,6-

dimethylheptyl), cyclohexyl, and the like, oras,

for example a 2-alkylamino-l-butanol of any of the above exemplifiedalkyl groups there are obtained the corresponding alpha-phenylbutyratehydrochlorides of 1-alkylamino-2-propanols, alpha-phenylbutyratehydrochlorides' of 2-alkylamino-l-propanols, alpha-phenylbutyratehydrochlorides of 3-alkylamino-l-propanols, alphaphenylbutyratehydrochlorides of 2-alkylamino- Z-methyl-l-propanols,alpha-phenylbutyrate hydrochlorides of 2-alkylamin0 1-butanols, and thelike.

1 Example '2. 1-(3-p6ntZ/lamin0)-2-propyl dzphenylacetate hydrochloridemelting at 141-142 C. was obtained by replacing the alkylaminoalkanoland the alphaphenylbutyryl chloride of Example 1 by the molal equivalentrespectively of 1-(3-pentylamino)-2-propanol and diphenylacetylchloride.

By replacing the alkylaminoalkanol of Example 2 by the molal equivalentof any (secondary) alkylamino-ethanol, -propanol or -butanol,- any ofeach of which is primary or secondary, there is obtained thecorresponding diphenylacetate hydrochlorides, such as, for example,2-(sec. butyl) amino-ethyl diphenylacetate hydrochloride, M. P. 154156C., 2-(2- pentylamino)-ethyl diphenylacetate hydrochloride, M. P.121-123 C., 2-(3-pentylamino) -ethyl.

diphenylacetate hydrochloride, M. P. 152.5-153.5 C., 2-[4(2,6-dimethylhepty1)aminol-ethyl diphenylacetate hydrochloride, M. P.119-121 0., 2-cyclohexylamino-ethyl diphenylacetate hydrochloride, M. P.176-177 C., 1--isopropylamino-2- propyl diphenylacetate hydrochloride,M. P. 184- 185 C., 1-(4-heptylamino)-2-propyl diphenylacetatehydrochloride, M. P. 119-120 C., 1-[4- (2,6 dimethylheptyl)aminol-2-propyl diphenylacetate hydrochloride, M. P. 167-169 C.,l-cyclohexylamino-2-propyl diphenylacetate hydrochloride, M. 'P. 183184C., 2-cyclohexylamino-1- butyl diphenylacetate hydrochloride, M. P. 127-128 0., 2-(3-penty1amino)-1-butyl diphenylace-- tate hydrochloride, M.P. 120.5122 C. and the like.

Similarly, by replacing the alpha-phenylbutyryl chloride of Example 1 orthe diphenylacetyl chloride of Example 2, or in any of the modificationsnoted in connection with either one of these two examples, by the molalequivalent of cinnamoyl chloride, there is obtained respectively thesecondary alkyl (secondary) amino alkyl cinnamate hydrochloride.

'In preparing the esters starting with an alkylaminoalkanol containing atertiary alcohol group, the desired secondary-alkylaminoalkanol havingthe tertiary alcohol group and containing the desired secondary-alkylsubstituent on its amino group is reacted with a substantial excess suchas a 50% excess of the acidyl halide or anhydride of cinnamic,diphenylacetic, alpha-cyclohexyl- 4 alpha-phenyl-acetic oralpha-phenylbutyric acids to form the corresponding N-acyl derivative ofthe selected alkylamino-alkanol, which amide is then rearranged to thecorresponding ester hydrochloride, for: example;-;- by boiling inabsolute alcohol with an excess .of concentrated hydrochloric acid. Suchprocedure may be illustrated by, but not restricted to, the followingexamples:

Example 3. 1 cycloheazylamino-Z-methyl-Z- propyl cinnamatehydrochloride.(a) A 50% excess of cinnamoyl chloride in 100 cc.methylene chloride was added rapidly to a vigorously stirred suspensionof 0;035 to 0.065 mole of l-cyclohexylamino--2rmethyl-2-propanol inabout 200 cc. of aqueous sodium hydroxide. The mixture was heated, withvigorous mechanical stirring, in a water bath so that the methylenechloride refluxed at 4045 C. for one hour, after which the reactionmixture layers were separated and the aqueous layer was then extractedwith methylene chloride. The combined methylene chloride solutions werewashed twice withwater and concentrated under vacuum to a syrupy liquidof constant weight, representing. a 76% yield of the N- cinnamoylderivative of l-cyclohexylamino-Z- methyl-2-propanol.

('b) 0.017 mole of this ,product was rearrangedv to the correspondingester hydrochloride by boiling with a 50%36XC8SS of concentratedhydrochloric acid in an alcohol solution for five min-,

utes; The solution was cooled and then vacuum distilled to dryness. Theresidue was dried by adding benzene and. reconcentrating under vacuum.The thus dried product was recrystallized frorn acetone in a-.-64%yield, M. P, 161

Example. 4'. 1-cyclohea:ylamino Z-methyl-Z- propyl diphenylacetatehydrochloride.The N- acyl derivative was obtained by theprocedure ofExample 3(a) by replacing the cinnamoyl chloride by thediphenylacetylchloride. The amide wasobtained in 84%;yield with M. P.of,154-155.5 C. after recrystallization from alcohol. 3.7 grams of thethus-formed N-acyl derivative was refluxed for one hour in25 cc.,absolute alcohol. containing 0.9 cc. of concentratedhydrochloric acid,cooled and filteredqtoremove anyunchanged amide. A yield of,r1cyclohexylamino-2-methyl-2- propyl .diphenylacetate hydrochloride wasobtained from the filtrate by distilling to dryness under vacuumand-,recrystallizing the residue from acetone. It melted at 1'72-1'7 4C.

Ezrample 5 -1 .eyeloheqcylamino-Z-methyl-2- propyl alphd-phenylbutyratehydrochloride. The N-acyl derivative was obtained by the procedure orExample 3(a) by replacing the cinnamoyl chloride by alpha-phenylbutyrylchloride. A 'l9% yield of the amide was obtained with M. P. 66.5-68 C;after recrystallization from ether and pentane. The esteris prepared byany of the above described methods of rearrangement.

Example 6. 1-cyclohexylc mino-2-methyZ-2- propyl-carba'nilatehydrochloride-The N-acyl derivative was prepared by a procedure similarto Example 3(a) by adding 4.8 grams ofphenyl isocyanate slowly to asolution of 6.8 grams of the aminoalcohol in methylene chloride. An 83%yield of the amide was-obtained, showing a M. P. 131.5-132.5 C. afterrecrystallization from benzene. 4.4 grams-'of this amide was dissolvedin cc. of chloroform and thesolution saturated With dry hydrogenchloride. .The solution was then heated-in a bathmaintained at 55 C. forseventy hours. The solution was then; vacuum evaporated 'to' dryness andtheresidue recrystalester, M. P. 19619'7 C. (with decomposition),

elsoinclu the nnarnetes. diehe a etates, alpha-cyclohxyl-alphaphenyl-acetates-v nd: alnh mheny bmymte ta n d; wi othersecondary-alkyl-aminoalkanols having a tertiaryalcohol; group, accordingto the procedure of Examples 3 through 5, such as:

l-cyclopentylamino 2 methyl-2-propyl cinnamate1-isopropylamino-2-methyl-Z-propylccinnamate 1- (3 -pentylamino) 2-methyl2-propyl cinnamate l- (Z-heptylamino) -2-methyl-2 -propylcinnamate 1- (2 -octylamino) -2-methyl-2-propyl cinnam ate ride.-Asolution of 7.1 g. ('0.03,mole) of alpha;

cyclohexylphenylacetyl chloride in g. of chloroform was added to asolution of 3.9 g. (0.03 mole) of 2-(2-pentylamino)-ethanol in 10 g. ofchloroform saturated with dry hydrogen chloride. The resulting solutionwas heated at 50 for forty-one hours. The solvent was removed undervacuum, and the residue crystallized slowly after stirring with pentaneand cooling. The yield of the product crystallized from acetone andether was 2.0 g. M. P. l09-111 C.

Similarly, by replacing the secondary alkyl- (secondary) amino alkanolof Example '7 by any other secondary alkyl(secondary) amino alkanoldescribed hereinabove there is obtained the correspondingalpha-cyclohexyl-alpha-phenyl-acetate hydrochloride of the selectedsecondary alkyl secondary amino alkanol.

The esters of the invention are thus prepared from a wide variety ofsecondary-alkyl(secondary) amino-alkanols selected from the -ethanols,'propanols and -butanols, which alkanols then include a wide variety ofsuch as the 2-secondaryalkyl-(secondary)amino-l-alkanols, and3-secondary-alkyl (secondary) aminol-alkanols, and alsol-secondary-alkyl(secondary) amino-2-alkanols, in all of which thealkanol group is selected from the ethanol, propanol and butanol groups,which alkanol groups may contain the secondary-alkylamino grouping asthe sole substituent or may contain additional substituents on thealkanol carbons, such as an alkyl radical, preferably a lower radical,on the 2- and 3- carbon atoms.

The various suitable secondary-alkyl(secondary) amino-ethanols,-propanols and -butano1s advantageously may be prepared by condensing aketone with a primary amino alcohol, with simultaneous or subsequentreduction, the mechanism of which is the formation of an intermediatealkylidene amino alcohol, or the formation of an intermediateoxazolidine or the formation of an intermediate mixture of both. Suchadvantageous procedure is described in my copending application Serial N0. 489,499, filed June 3, 1943, now abandoned, reference to which ismade for details of such procedure.

While the various Examples 1 through '7 show the preparation of thehydrochloride of the various esters, if the free base is desiredinstead, it is prepared by dissolving or suspending the hydrochloride ina small volume of alcohol, diluting with Water and treating with anexcess over the t ichiona tric; uant y or sadi ar qx et and recoveredtherefrominknown manner.

example, in benzenethere is added the stoichi o; metric quantity of theparticular acidv of which, he a di on. lt is desir n the sol ent movedby evaporation, under-vacuum if desired,

and the desiredaddition salt; obtained by crystallization.

- The anesthetic compounds of the invention are, the free amines, that,is,. the free bases. Qrdia narily they are used in the form of additionsalts, for: example, as a hydrochloride, sulfate, sulfamate, tartrate,glycolate or other addition. salt,

as, the free amines or bases are quite insoluble in water.Theselectedsalt should have sufficient solubility in water to becompletelysoluble in the,

concentrations used, usually of. the :order of 11% or less. Thehydrochlorides and the glycolates are among those particularlytherapeuticallyefe. fective. The esters in which thesecondary-amylsubstituent on the amino group contains less than 11carbon atoms are particularly effective.

While these various individual illustrations of the esters of theinvention have been separately named as a certain ethyl, propyl or as acertain butyl acid ester, as exemplified in starting withZ-isopropylamino-ethyl alpha-phenylbutyrate as in Example 1 andcontinuing from there through the disclosure ending with2-(2-pentylamino)- ethyl alpha-cyclohexyl-alpha-phenyl-acetate, in-

sofar as nomenclature is concerned each of the various individual estersembraced in the invention is either an ester of asecondary-alkyl(secondary) amino-ethanol, secondary-a1kyl secondary)amino-propanol or of a secondary-alkyl- (secondary) amino-butanol.

What is claimed is:

1. Esters of secondary alkyl(secondary) amino alcohols, of the generalformula X-COOR1NHR, in which R represents a secondary alkyl groupattached to the amino nitrogen and has a total of at least three andless than eleven carbon atoms, R1 is a divalent alkylene group having atotal of from two through four carbon atoms and with at least two carbonatoms linked in sequence between the oxygen and the nitrogen, and X isselected from the group consisting of the styryl radical, diphenylmethylradical, alpha-cyclohexyl-alpha-phenylmethyl radical andalphaphenylpropyl radical.

2. Esters of secondary alkyl(secondary) amino alcohols, as in claim 1,in which X is the styryl radical.

3. Esters of secondary alkyl(secondary) amino alcohols, as in claim 1,in which X is the diphenyl methyl radical.

4. Esters of secondary alkyl(secondary) amino alcohols, as in claim 1,in which X is the alphaphenylpropyl radical.

5. Esters of secondary alkyl(secondary)amino alcohols, of the generalformula in which R represents a secondary alkyl group attached to theamino nitrogen and has a total of at least three and less than elevencarbon atoms, R1 is a divalent alkylene group having a total of from twothrough four carbon atoms with 'at least two carbon atoms linked insequence between the oxygen and the nitrogen, and R2 is a divalentaliphatic hydrocarbon radical selected from the vinylene and propylideneradicals.

for

- 6. Esters of secondary alkyl(secondary) amino alcohols, of the generalformula X-COOR1NHR in which R is an alicyclic radical having less thaneleven carbon atoms and having at least five and less than seven carbonatoms linked together in sequence to form the alicyclic ring, R1 is adivalent alkylene group havin a total of from two through four carbonatoms and with at least two carbon atoms linked in sequence between theoxygen and the nitrogen, and X is selected from the group consisting ofthe styryl radical, diphenylmethyl radical,alpha-cyclohexyl-alphaphenylmethyl radical and alpha-phenylpropylradical. a

7. Esters of secondary alkyl(secondary) amino alcohols, as claimed inclaim 6, in which X is the styryl radical.

- 8. Esters of secondary alkyl(secondary) amino alcohols, as claimed inclaim 6, in which X is the diphenylmethyl radical.

9. Esters of secondary alkyl(secondary)amino alcohols, as claimed inclaim 6, in which X is the alpha-phenylpropyl radical.

8 10. 2-(2-pentylamino) -ethyl diph'enylaceta'te hydrochloride. 1 11.1-cyclohexylamino-Z-propyl diphenylacetate hydrochloride. 1 12.'2-cyclohexylamino ethyl alpha phenylbutyrate hydrochloride. ARTHUR C.COPE.

REFERENCES CITED The following references are of record in the file ofthis patent: I 1 I x UNITED STATES PATENTS f v Number Name v Date1,817,640 Brill Aug-4, 1931;

2,219,796 Viaud' Oct. 29, 1940 2,265,184 Miescher et al. Dec 9, 19412,339,914 Cope "Jan. 2 5, 1 944' 2,399,506 Pierce "Apr. 30,1940

OTHER REFERENCES. i t

Pierce et al., Jour: Amer. Chem; 'Soc.,yol.l* 6'7'(1943), pages 408-409.

